Obesity and its associated metabolic syndrome attained epidemic status in U.S. adolescents with the potentiality of earlier onset of their co-morbidities, including type 2 diabetes and cardiovascular disease. Our group is currently funded to determine the quantitative genetics of their biologic precursors and the effects of the 3q27 QTL positional candidate gene's variances on its expression in the adult members of 177 our highly informative families. The specific objective of this application is to include their pre-, peri-, and post- adolescent descendents. This objective is pursued via three complementary hypotheses and specific aims. Hypothesis 1: "Biologic precursors and clinical components of the adolescent's metabolic syndrome are genetically intercorrelated." In Specific Aim 1, quantitative genetics and intercorrelations of the biologic precursors (total body fat and muscle, abdominal, visceral, and subcutaneous fat distribution, indices of insulin dynamics and sensitivity, LDL and HDL density profiles, circulating levels of cytokines/adipokines, and endothelial hyperactivity/adhesion markers) and the clinical components (BMI, waist and hip circumference, fasting plasma glucose and insulin, lipids and lipoproteins, and resting pulse and blood pressure) are determined. Hypothesis 2: "Polymorphisms in APM1, PSARL and the newly identified positional genes ABCC5, HTR3E, KCNMB3, CCDC5 and KIAA0804, influence expression of the adolescent's metabolic syndrome." In Specific Aim 2, all individuals are genotyped for all polymorphisms identified by comprehensively resequenced candidate genes and the causally associated polymorphisms are determined. Hypothesis 3: "Causally associated polymorphisms of the 3q27 positional candidate gene's expression are influenced by the adolescent's stage and age." In Specific Aim 3, the genotype- by-adolescent stage and -by-age interactions are determined from the adolescent's and their adult family member's data. The combined outcome should provide a global insight into the genetic origin of this syndrome and its co-morbidities. Relevancy to Agency's Mission: Information gained by this project will help contribute to understanding the genetic origins of the metabolic syndrome, now considered the major risk factor for type 2 diabetes and cardiovascular disease. This knowledge should assist in the development of new preventative means and/or therapies.